Project Summary Understanding molecular mechanisms that govern the aging process is critical in the face of the ever-increasing incidence of age-related diseases. Loss of epigenetic regulation with age has emerged as a hallmark of aging, but little is known about the mechanisms linking chromatin alterations to longevity. Recently, in collaboration with the Brunet lab at Stanford University, we demonstrated that chromatin changes in the Caenorhabditis elegans germline, specifically a deficiency in trimethylation of lysine 4 on histone H3 (H3K4me3) via the Complex Proteins Associated with Set1 (COMPASS), induce changes in expression of mTOR targets which orchestrate a metabolic shift in somatic tissues to extend lifespan via a specific enrichment of mono-unsaturated fatty acids (MUFAs). This effect is mediated by the SREBP1/SBP-1 transcription factor, which is activated through COPII- mediated ER-to-Golgi transport. Recent data in mammals highlighted a critical role for CREB regulated transcriptional coactivator (CRTC)2 in COPII trafficking, while we have shown that the sole C. elegans CRTC modulates aging and energetic metabolism. Excitingly, my preliminary data indicate that CRTC-1 specifically regulates lifespan extension in H3K4me3-deficient animals, establishing a novel role of CRTC-1 in the epigenetic regulation of aging. My long-term goal is to understand how epigenetic regulation integrates environmental and internal signals to influence gene expression and downstream cellular processes to promote longevity and transgenerational benefits. This proposal will use a combination of genetics, microscopy, metabolomics, and genomic approaches to uncover the molecular mechanisms that mediate H3K4me3-dependent longevity. Aim 1 will define the spatiotemporal requirements of the COMPASS chromatin complex to mediate longevity and its effectors such as CRTC-1, SREBP1/SBP-1 and mTOR targets. To complement these studies, Aim 2 will identify the downstream molecular mechanisms and metabolic changes that a specific function of CRTC-1 regulates to promote H3K4me3-dependent longevity. The independent R00 phase will focus on studying transgenerational mechanisms downstream of the COMPASS-mTOR-CRTC pathway to promote longevity. The conservation of all these components will allow me here to translate these findings into mammalian systems to identify the cellular and physiological responses that epigenetic modifications control to promote longevity. Together, these findings will serve as the foundation of my research program and will launch the beginning of my independent research career. My primary mentor, Dr. William Mair will provide important scientific and career guidance to ensure my success. My advisors and collaborators complement Dr. Mair?s expertise and will help me reach my career and research goals. The K99/R00 award constitutes a unique opportunity for my advance in the academic track. It will help me to consolidate an innovative niche in the study of epigenetics of aging and provide me with the necessary academic and technical training to launch my career as an independent investigator.